Methamphetamine (MA) dependence is a significant source of deleterious consequences to individual and public health including HIV infection, psychological distress, and cardiovascular disease (Cruickshank and Dyer 2009), particularly in the Western United States. Behavioral treatments, including cognitive behavioral therapy (CBT) and contingency management (CM) are available (Lee and Rawson 2008) but are modestly effective. Medications that have efficacy in reducing MA use that could be integrated with behavioral therapies would represent a significant advancement in treatment. Cholinergic mechanisms are important in the neurobiology of stimulant dependence including MA (Hiranita, Nawata et al. 2008;Williams and Adinoff 2008). Varenicline is a 1422 nicotinic receptor partial agonist and 17 nicotinic receptor full agonist that is approved for cigarette smoking cessation (Gonzales, Rennard et al. 2006) and shows promise for treating alcohol dependence (McKee, Harrison et al. 2009). Varenicline may be effective for the treatment of MA dependence due to dopaminergic effects, relief of glutamatergic and cognitive dysfunction, and activation of nicotinic cholinergic systems. Building upon this rationale and preliminary experiences (in a Phase I clinical trial and a pilot Phase II trial), the investigators propose a randomized placebo-controlled, double-blind Phase II clinical trial of varenicline for MA dependence. Similar to smoking cessation treatment, study medication will be titrated to 1 mg BID over one week after which participants will take varenicline (1 mg BID) or placebo during a brief inpatient MA-detoxification period (4 nights) followed by 8 additional weeks of outpatient treatment with CBT. The brief inpatient detoxification is an important design innovation, as it facilitates all subjects to achieve a brief period of abstinence, to resolve initial withdrawal symptoms, and to allow measurement of varenicline efficacy as a MA withdrawal treatment. The subsequent 8-week outpatient treatment period allows the investigators to test varenicline for efficacy in preventing MA relapse during early abstinence. Although smoking cessation treatment is not provided, potential effects of varenicline on cigarette smoking will be assessed. PUBLIC HEALTH RELEVANCE: In Los Angeles County, methamphetamine accounts for more admissions to publicly funded treatment than any other substance, including alcohol. There is a significant public health need for medications that could optimize outcomes of behavioral therapies for dependent individuals seeking abstinence from methamphetamine. This Phase II clinical trial will collect data describing the efficacy and safety of varenicline (CHANTIX) for the treatment of methamphetamine dependence.